Dr Regina P. Berba discusses the common infectious emergencies in SLE

1. SEVERE
INFECTIONS
in
LUPUS
as
a
RHEUMATOLOGIC
EMERGENCY
Regina Berba MD MSc
Sections of Adult Medicine & Infectious Diseases

2. ARE
LUPUS
PATIENTS
AT
HIGHER
RISK
FOR
MORE
SEVERE
INFECTIONS?

4. Overview of the Pathogenesis of Systemic Lupus Erythematosus.
Tsokos GC. N Engl J Med 2011;365:2110-2121
PATHOGENESIS
OF
SLE

5. Chromosome Loci and Genes Associated with SLE.
Tsokos GC. N Engl J Med 2011;365:2110-2121
Chromosomal
and
Genetic
Uniqueness
in
SLE

6. SLE.
Tsokos GC. N Engl J Med 2011;365:2110-2121
Translates
to
a
massive
aberrant
in#lammatory
&
immunocompromised
response

7. Treatment Approaches for SLE.
Tsokos GC. N Engl J Med
2011;365:2110-2121
Treatment
of
SLE
also
contributes
to
additional
risks
for
infections

8. Increased
susceptibility
of
LUPUS
patients
to
infections:
• IMMUNE
DYSFUNCTION
FROM
ILLNESS
• Phagocy7c
dysfunc7on
• Lymphopenia
• Decreased
cytokine
produc7on
• Decreased
immunoglobulin
• Impaired
func7oning
of
complement
system
• Func7onal
asplenia
• IMMUNOSUPPRESSION
FROM
TREATMENT
• Glucocor7coids
• Other
immunosuppressive
drugs

9. “SLE
as
an
Emergency”
“An
emergency
in
medicine
can
be
defined
as
a
situa7on
that
endangers
life,
or
an
organ
system,
or
quality
of
life.
In
that
sense,
SLE
ITSELF
IS
AN
EMERGENCY.”
hOp://www.apiindia.org/pdf/pg_med_2004/chapter_46.pdf

10. Among
the
emergencies,
infections
are
probably
the
most
commonly
encountered
• Infec7ons:
59/100
pa7ent-­‐years
• Usually
mul7ple
sites
• May
overlap
with
disease
ac7vity/flare
• Most
common
sites:
• UTI
• Pneumonia
• Joint
infec7ons
• CNS
infec7ons
• Abdominal
infec7ons
• Skin
hOp://www.apiindia.org/pdf/pg_med_2004/chapter_46.pdf

11. Bacteria
accounts
for
80-­‐90%
• Streptococcus
pneumoniae
• Staphylococcus
aureus
• Ecoli
• Salmonella
• Klebsiella
• Pseudomonas
• Mycobacterium
tuberculosis
hOp://www.apiindia.org/pdf/pg_med_2004/chapter_46.pdf

12. Bacterial
causes
of
SLE
infections
GRuiz-­‐Irastorza,
NOlivares,
I
Ruiz-­‐Arruza,
A
Mar6nez-­‐Berriotxoa,
MV
Egurbide,
Caguirre
Predictors
of
major
infec7ons
in
systemic
lupus
erythematosus
Arthri&s
Research
&
Therapy
2009,
11:R109

13. Salmonella
infections
• Bacteremia
with
extraintes7nal
manifes7ona7ons
• UTI
• Myco7c
aneurysm
• Arthri7s
• Pericardi7s
• Osteomylei7s
• Sob
7ssue
abscesses
• Mortality
as
high
as
25%
hOp://www.apiindia.org/pdf/pg_med_2004/chapter_46.pdf

14. • September
1996
to
May
1997
• Mexico
City
• 180
pa7ents
visited
ER
• 164
females
• Mean
age:
31.7
• Mean
Mex
SLEDAI
score
3.8
• Mean
SLICC-­‐ACR
1.3
• Most
common
CC:
Fever
• 49
SLE
pa7ents
admiOed:
2
deaths

15. Hospitalized
vs
non-­‐hospitalized:
Risk
Factors
• Compliance
(7.6
vs
9
p<0.0001)
• Malar
Rash
(57%
vs
82%
p<0.0008)
• Disease
severity
in
Physician
global
assessments
(5.6
vs
2.1
p<0.0001)
• Beck
depression
inventory
(21
vs
16
p<0.01)
• Pa7ents
level
of
formal
educa7on
• Chloroquine
daily
dose
intake
(45
vs
77
mg
p<0.04)

16. 2007-­‐2010
China
131
SLE
ER
visits
16.8%
mortality
Clinical
Rheumatology
2011

17. Predictors
of
mortality
• Older
age
>45
years
• Longer
dura7on
of
disease
• Presence
of
pulmonary
hypertension
• Presence
of
renal
insufficiency
• Presencey
of
invasive
infec7on
• Higher
organ
damage
index
(SLICC
3.86
vs
0.93
p<0.001)
• Lower
diseas
ac7vity
(SLE-­‐DAI
11.5
vs
16.5,
p=0.015)
Chen
et
al
“Severe
systemic
lupus
erythematosus
in
emergency
department:
a
retrospec7ve
single-­‐center
study
from
China”
Clinical
Rheumatology
2011

18. Canadian
experience
single
center:
Cohort
of
665
SLE
patients
5
yrs
• 124
deaths
(18.6%)
• The
overall
survival
rates:
• 5
year:
93%
• 10
year:
85%
• 15
year:
79%
• 20
year:
68%
• Most
common
causes
of
deaths:
• Infec7on
40
(32%)
• SLE
in
20
(16%)
• Acute
vascular
event
19
(15.4%)
• Malignancy
8
(6.5%)
• Organ
failure
6
(4.8%)
Abu-­‐Shakra
M,
Urowitz
MB,
Gladman
DD,
Gough
J
J
Rheumatol
1995,
22(7):1259-­‐1264

19. Risk
of
Death
in
SLE
due
to
Infections
• 7
Countries
in
Europe
• At
the
end
of
10
years,
68
pa7ents
have
died
(6.8%)
• Causes
of
death:
• SLE
26.5%;
• Thromboses
26.5%,
•
infec7ons
25%

20. SLE
admissions
to
ICU:
Infection
Lash
A
and
B
Lusk
“Systemic
Lupus
Erythematosus
in
the
Intensive
Care
Unit”
Crit
Care
Nurse
2004,
24:56-­‐65.
hOp://www.cconline.org

21. MOST
COMMON
REASON
FOR
ICU
ADMISSION:
INFECTION
• Thong
series
1999-­‐2000:
62%
admission
due
to
infec7on
• Noel
et
al:
66%
of
SLE
pa7ents
for
admission
were
due
to
infec7on;
14%
needed
ICU
• Use
of
steroids
(p<0.005)
• Use
of
pulse
treatment
with
cyclophosphamide
(p<0.003)
• Plasmapheresis
(p<0.01)
• Ansell:
37%
of
SLE
admissions
to
ICU
were
due
to
infec7on:
pneumonia,
UTI,
meningi7s
Noel
V,
Lortholary
O,
Cassassus
P,
et
al.
Risk
factors
and
prognos7c
influence
of
infec7on
in
a
single
cohort
of
87
adults
with
systemic
lupus
erythematosus.
Ann
Rheum
Dis.
2001;60:1141-­‐1144.
Thong
BY,
Tai
DY,
Goh
SK,
Johan
A.
An
audit
of
pa7ents
with
rheuma7c
disease
requiring
medical
intensive
care.
Ann
Acad
Med
Singapore.
2001;30:254-­‐259.
Ansell
SM,
Bedhesi
S,
Ruff
B,
et
al.
Study
of
cri7cally
ill
pa7ents
with
systemic
lupus
ery-­‐
thematosus.
Crit
Care
Med.
1996;24:981-­‐986.

22. Survival
curves
of
SLE
at
ER
Chen
et
al
“Severe
systemic
lupus
erythematosus
in
emergency
department:
a
retrospec7ve
single-­‐center
study
from
China”
Clinical
Rheumatology
2011

23. Approach
to
SLE
Patients
with
Severe
Infections

24. RECOMMENDATIONS
FOR
SEPTIC
LUPUS
PATIENTS

25. - Dellinger RP, et al. Surviving Sepsis Campaign: International Guidelines for Management of Severe
Sepsis and Septic Shock: 2012. Crit Care Med. Feb 2013; 41(2): 580-637.

26. Annals
of
Emergency
Medicine
Volume
63,
Issue
1,
Pages
35-­‐47
(January
2014)
DOI:
10.1016/j.annemergmed.2013.08.004

27. Review Article: Critical Care Medicine
Severe Sepsis and Septic Shock
Derek C. Angus, M.D., M.P.H., and
Tom van der Poll, M.D., Ph.D.
N Engl J Med
Volume 369(9):840-851
August 29, 2013

28. †National Center for Health Statistics, 2001.
§American Cancer Society, 2001. *American Heart Association.
2000.
‡Angus DC et al. Crit Care Med. 2001;29(7):1303-1310.
AIDS* Colon Breast
Cancer§
CHF†
Severe
Sepsis‡
Cases/100,000
0
50
100
150
200
250
300
Incidence of Severe Sepsis Mortality of Severe Sepsis
0
50,000
100,000
150,000
200,000
250,000
Deaths/Year
AIDS*
Severe
Sepsis‡
AMI†
Breast
Cancer§
SEPSIS
in
comparison
with
other
major
diseases

29. The
OVERARCHING
MESSAGE
OF
THE
SEPSIS
GUIDELINES:
• The
SPEED
and
APPROPRIATENESS
of
therapy
administered
in
the
INITIAL
hours
aOer
severe
sepsis
develops
• …significantly
INFLUENCE
clinical
outcomes.

30. WHAT
IS
APPROPRIATE
SEPSIS
MANAGEMENT
FOR
VERY
ILL
SLE
PATIENTS?

31. Recognizing
Sepsis
among
SLE
patients

32. TERMINOLOGY
" Systemic
Inflammatory
Response
Syndrome
(SIRS)
" Temp
>
38
or
<
36
" HR
>
90
" RR
>
20
or
PaCO2
<
32
" WBC
>
12
or
<
4
or
Bands
>
10%
" Sepsis
" The
systemic
inflammatory
response
to
infec7on.
" Severe
Sepsis
" Organ
dysfunc7on
secondary
to
Sepsis.
" e.g.
hypoperfusion,
hypotension,
acute
lung
injury,
encephalopathy,
acute
kidney
injury,
coagulopathy.
" Sep6c
Shock
" Hypotension
secondary
to
Sepsis
that
is
resistant
to
adequate
fluid
administra7on
and
associated
with
hypoperfusion.
Bone, R., Balk, R., Cerra, F., Dellinger, R., Fein, A., Knaus, W., Schein, R., et al. (1992). Definitions for sepsis and organ failure and guidelines for the
use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of
Critical Care Medicine. Chest, 101(6), 1644–1655."
TWO
out
of
four
criteria
acute
change
from
baseline

33. Infection,
SIRS,
Sepsis
Bone, R., Balk, R., Cerra, F., Dellinger, R., Fein, A., Knaus, W., Schein, R., et al. (1992). Definitions
for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The
ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society
of Critical Care Medicine. Chest, 101(6), 1644–1655."

34. SEPSIS
PATHOGENESIS
Unbalanced
Immune
Reac7on
Tissue
Factor
Procoagulant
State
Microvascular
Thrombosis
Mediators
of
Inflamma7on
ROS
Vasodila7on
Capillary
Leak

35. Angus DC, van der Poll T. N Engl J Med 2013;369:840-851
HOST
RESPONSE
IN
SEVERE
SEPSIS

36. Angus DC, van der Poll T. N Engl J Med 2013;369:840-851
Organ
Failure
in
Severe
Sepsis
and
Dysfunction
of
the
Vascular
Endothelium
and
Mitochondria.

37. Organ
failure
in
SEPSIS
Vincent, J.-L., Sakr, Y., Sprung, C. L., Ranieri, V. M., Reinhart, K., Gerlach, H., Moreno, R., et al. (2006). Sepsis in European intensive
care units: results of the SOAP study. Critical Care Medicine, 34(2), 344–353."
P/F
Platelets
Bili
BP
GCS
Cr/UOP

41. MAJOR
CHANGES
IN
THE
NEW
SEPSIS
GUIDELINE
• Use
of
protocolized
quan7ta7ve
resuscita7on
with
specific
physiologic
targets
• Preferen7al
use
of
crystalloids
(with
or
without
albumin)
for
volume
resuscita7on
• Preferen7al
use
of
norepinephrine
• Addi7on
of
lactate
clearance
as
a
marker
of
7ssue
hypoperfusion
• Decreased
emphasis
on
the
use
of
cor7costeroids

42. Figure
2
Source:
Annals
of
Emergency
Medicine
2014;
63:35-­‐47
(DOI:10.1016/j.annemergmed.2013.08.004
)
Copyright
©
2014
American
College
of
Emergency
Physicians
Terms
and
Condi7ons
Surviving
Sepsis
Bundle

43. ESSENTIALS
IN
SEPSIS
MANAGEMENT
OF
LUPUS
PATIENTS
• Initial
Resuscitation
• Fluids
• Pressors
• Microbial
Diagnosis
• Antimicrobial
Therapy
• Primer
on
Antibiotics
• Source
Control
• Infection
Prevention

44. INITIAL
RESUSCITATION
FOR
SEPTIC
LUPUS
PATIENTS
• 1)
Protocolized
quan7ta7ve
resuscita7on
of
pa7ents
with
sepsis-­‐induced
7ssue
hypoperfusion
(defined
as
hypotension
persis7ng
aber
ini7al
dluid
challenge
or
blood
lactate
concentra7on
>
4mmol/L).
Goals
during
the
first
6
hours
of
resuscita7on:
• A)
Central
venous
pressure
8-­‐12
mm
Hg
• B)
Mean
arterial
pressure
(MAP)
>/=
65mm
Hg
• C)
Urine
output
>/=
0.5ml/kg/hr
• D)
Central
venous
or
mixed
venous
O2
satn
70%
or
65%
respec7vely
(Grade
1C)
• In
pa7ents
with
elevated
lactate
levels
targe7ng
resuscita7on
to
normalize
lactate
(Grade
2C)

45. FLUID
THERAPY
OF
SEVERELY
SEPTIC
LUPUS
PATIENTS
• 1)
Crystalloids
as
the
ini7al
fluid
of
choice
(1B)
• 2)
Against
the
use
of
hydroxyethyl
starches
(1B)
• 3)
Albumin
may
be
used
when
pa7ents
require
substan7al
amounts
of
crystalloids
(2C)
• 4)
Ini7al
fluid
challenge
with
sepsis-­‐induced
hypoperfusion
with
suspicion
of
hypovolemia
to
achieve
a
minimum
of
30ml/kg
of
crystalloids
(1C)

46. Use
of
Vasopressors
• 1)
Vasopressor
therapy
to
target
MAP
65mmHg
(1C)
• 2)
Norepinephrine
is
the
first
choice
vasopressor
(1B)
• 3)
Epinephrine
added
to
or
poten7ally
subs7tuted
when
addi7onal
agent
is
needed
to
maintain
adequate
BP
(2B)
• 4)
Vasopressin
0.03
units/min
can
be
added
to
NE

47. AntimicrobialTherapy

48. MICROBIAL
DIAGNOSIS
• 1)
Cultures
as
clinically
appropriate
BEFORE
an7microbial
therapy
if
no
significant
delay
(>45min)
in
the
start
of
an7microbial
(Grade
1C).
• At
least
2
sets
of
blood
CS
be
obtained
before
an7bio7cs
(Grade
1C)
• 2)
Imaging
studies
performed
promptly
to
confirm
a
poten7al
source
of
infec7on
(UG).

49. Inadequate
antibiotic
therapy:
A
RISK
FACTOR
FOR
MORTALITY
Vallés et al. Chest 2003 123:1615–1624

50. Hospital
Mortality
by
Time
to
Antibiotics

51. Variable
Odds Ratio
95% CI
P Value
Broad-spectrum antibiotics
0–1 hours
0.67
0.50–0.90
0.008
1–3 hours
0.80
0.60–1.06
0.127
3–6 hours
0.87
0.62–1.22
0.419
No antibiotic in the first 6
1
Fluid challenge in the event of
hypotension
1.01
0.73–1.39
0.966
Low-dose steroids for persistent
hypotension despite fluid
resuscitation and/or lactate .36
mg/dl
1.04
0.85–1.28
0.688
Impact
of
timely
antibiotic
interventions
in
severe
sepsis
on
hospital
mortality
Am J Respir Crit Care Med Vol 180. pp 861–866, 2009

52. 2154 patients with septic shock,
78.9% got effective antimicrobial therapy
Delay in treatment (hours) from onset of hypotension
to effective antimicrobial therapy
-Kumar et al. Crit Care Med. 2006:34
Duration
of
hypotension
before
appropriate
therapy
and
association
with
mortality
Survivial(%)
0
10
20
30
40
50
60
70
80
90
0.5 1 2 3 4 5 6
Each hour of delay
carries 7.6% reduction in
survival

53. Antibiotic
timing
and
mortality
" No randomized-controlled data
Gaieski DF, Mikkelsen ME, Band RA, et al. Impact of time to
antibiotics on survival in patients with severe sepsis or septic
shock in whom early goal-directed therapy was initiated in the
emergency department*. Critical Care Medicine 2010;38(4):
1045–53. "
Kumar A, Roberts D, Wood KE, et al. Duration of
hypotension before initiation of effective
antimicrobial therapy is the critical determinant of
survival in human septic shock*. Critical Care
Medicine 2006;34(6):1589–96. "
Time
from
EDGT
qualifica7on
to
ABX
Time
from
hypotension
to
appropriate
ABX

54. • Intravenous
an7bio7c
therapy
be
started
as
early
as
possible
and
within
the
first
hour
of
recogni0on
of
sep7c
shock
(1B)
and
severe
sepsis
without
sep7c
shock
(1C).
Antibiotic
Therapy
for
Septic
LUPUS
Patients

55. Empiric
Antibiotic
Therapy
• 1)
Start
effec7ve
IV
an7bio7cs
within
the
first
hour
of
recogni7on
of
sep7c
shock
(1B)
and
severe
sepsis
without
sep7c
shock
(1C)
• 2)
Ini7al
empiric
an7bio7c
therapy
of
one
or
more
drugs
that
have
ac7vity
against
all
likely
pathogens
(bacterial
/or
fungal/or
viral)
and
that
penetrate
in
adequate
concentra7on
into
7ssues
presumed
to
be
the
source
of
sepsis
(1B)

56. Empiric
Antibiotic
Therapy
• 3)
Combina7on
empirical
therapy
for
neutropenic
pa7ents
with
severe
sepsis
92B)
and
for
pa7ents
with
difficult-­‐to-­‐treat
mul7drug
resistant
bacterial
pathogens
such
as
Acinetobacter
or
Pseudomonas
(2B).
• 4)
For
pa7ent
with
sever
infec7ons
asociated
with
respiratory
failure
and
sep7c
shock,
combina7on
therapy
with
an
extended
spectrum
beta
lactam
and
either
aminoglyocside
or
fluroquinolone
is
for
P
aeruginosa.
• 5)
A
combina7on
of
betalactam
and
macrolide
should
e
given
to
pa7ents
with
sep7c
shock
from
bacteremic
Streptococcus
pneumoniae
infec7ons
(2B).

57. OTHER
SUPPORTIVE
MEASURES
• Ven7latory
support
• Renal
replacement
therapy
• Bicarbonate
therapy
• Blood
products
• Seda7on,
pain
relief
• Glucose
control
• DVT
prophylaxis
• Stress
ulcer
prophylaxis
• Nutri7on

58. IS
IT
AN
INFECTION
OR
A
LUPUS
FLARE?
THE
REAL-­‐LIFE
CHALLENGES

59. IS
IT
CNS
INFECTION
OR
LUPUS
CEREBRITIS?
• In
Korea,
1420
SLE
pa7ents
were
followed
• 20
pa7ents
with
CNS
infec7on
• 11/20
:
Cryptococcus
neoformans
• Predictors:
• Older
age
group
(p=
0.025)
• Altered
mental
status
(p<0.005)
• Plasma
leukocytosis
(p
=
0.037)
• Neutrophila
(p
=
0.020)
• CSF
pleocytosis
(p
=
0.044)
• Low
CSF
Glucose
(p=
0.036)
Lupus
April
2011
vol.
20
no.
5
531-­‐536

60. Is
it
TB
or
is
it
Lupus?
Philippines
:
Retrospec7ve
study
390
pa7ents
with
SLE
• 13.8%
ac7ve
TB
• 74%
Pulmonary
TB
• Disseminated
TB
=
higher
lupus
ac7vity
index
and
more
aggressive
disease
• Victorio-­‐Navarra
ST,
Dy
EE,
Arroyo
CG,
Torralba
TP.
Tuberculosis
among
Fil
ipino
pa7ents
with
systemic
lupus
erythematosus.
Semin
Arthri7s
and
Rheum.
1996;26:628–34.

61. When
to
do
Tuberculin
Testing

62. How
to
interpret:
what
to
do
• There
should
be
no
sign
of
ac7ve
TB
• TREAT
with
9mos
Isoniazid
when:
• If
PPD
is
>10mm
• If
PPD
is
>5mm
in
those
who
will
take
15
mg
prednisone
daily
for
at
least
3
mos
• In
endemic
countries:
regardless
of
PPD,
treatment
of
Latent
TB
decreases
risk
of
ac7ve
TB
by
70%
if
prednisone
at
least
15mg/day
will
be
given
for
>
3mos
American
Thoracic
Society
Barber
et
al
Current
Opin
Rheumatolo
2011;
23(4):358-­‐365.

63. Is
it
infective
endocarditis
or
Libman-­‐
Sacks?

64. IS
IT
HIV
OR
LUPUS
ARTHRITIS
OF
THE
ARYTENOIDS?
HIV
and
Lupus
Erytheamtosus
Indian
J
Dermatolog
2008;
53(2):80-­‐82

65. NO
Guideline
for
Lupus
Patients!
PROPOSED
CHECKLIST
TO
PREVENT
INFECTIONS:
ü Yearly
influenza
shot
ü Pneumococcal
vaccina7on
ü Regular
pap
smears
to
screen
for
cervical
dysplasia
caused
by
HPV
ü HPV
vaccina7on
as
per
recommenda7ons
for
the
general
popula7on
ü TB
skin
test/PPD
prior
to
star7ng
immunosuppressive
agents
and
treatment
with
isoniazid
(INH)
for
pa7ents
with
latent
TB
infec7on.
ü Hepa77s
B
serology
at
baseline
in
all
pa7ents.
ü Hepa77s
C
serology
at
baseline
in
pa7ents
with
risk
factors.
ü HIV
serology
at
baseline
in
pa7ents
with
risk
factors.
ü Screening
for
strongyloides
in
pa7ents
from
endemic
areas
(strongyloides
serology)
prior
to
star7ng
immunosuppressive
agents
and
treatment
with
ivermec7n
if
infected.
Barber
C,
LGWayne,
PRFor7n.
Infec7ons
in
the
Lupus
Pa7ent:
Perspec7ves
on
Preven7on.
Curr
Opin
Rheumatol.
2011;23(4):358-­‐365.

66. Is
it
possible
to
do
all
these
in
the
Philippines
and
in
our
institution?
Of
course
OF
COURSE!

67. In
summary:
• Infec6ons
represent
14-­‐50%
of
cause
of
all
hospitaliza6ons
of
SLE
pa6ents
• Infec6ons
represent
significant
cause
of
mortality
• Aggressively
diagnose
and
treat
infec6ons,
even
in
situa6ons
where
dilemma
exists
• Preven6on
of
some
infec6ons
may
be
possible.

68. Let’s
Save
Lives!
Make
Our
Lupus
Patients
Survive
Sepsis